The present invention relates to a new combined preparation for the treatment of neoplasic diseases or of infectious diseases.
The present invention describes sequences of conventional treatments of cancer or infections and of immunotherapies reversing or preventing chemoresistance and allowing long lasting therapeutic responses.
In conventional therapy, residual tumor cells or infectious agents are left undamaged due to chemoresistance or due to the fact that these cells are shaded in protected areas or located in hypoxic areas poorly vascularized and not accessible to conventional treatments. The genetic instability and heterogeneity of tumors and micro-organisms indeed allow them to adapt and to develop resistance to therapies.
The beneficial effects of chemotherapy can be compromised by cellular mechanisms that allow infectious agents or neoplasic tissue to evade the toxicity of drugs. In some cases, pleiotropic resistance to a variety of unrelated drugs has been observed, and this phenomenon has been called multidrug resistance.
Resistance to chemotherapy, whether it is intrinsic or acquired, is a major cause of failure in the curative treatment of chronic infections or neoplasic malignancies. Among the most active anti-cancer agents used in the treatment of haematological malignancies are some natural toxin-derived drugs, such as the anthracycline daunorubicin or adriamicin, the epipodophyllotoxins, taxoter derivatives, the vinca alkaloid vincristine, cisplatin, fluorouracils.
Development of cross-resistance to these structurally and functionally unrelated drugs, called multidrug resistance, is frequently observed in second or third intention cytotoxic treatment of cancer.
Multiple drug resistance of infectious agents and particularly of bacteria to antibiotics such as penicillins, xcex2-lactamines, cephalosporines, aminoglucosides, macrolides and sulfamides, is more and more often seen in hospitals.
Monocyte derived cells (MDCs) are immune cells such as obtained by culture of blood mononuclear cells in non adherent gas permeable plastic or Teflon bags for 5 to 10 days at 37xc2x0 C. in O2/CO2 atmosphere. Their culture medium (RPMI, IMDM, AIM5 (Gibco) or X-VIVO (Biowhittaker)) contains eventually cytokines or ligands as defined in patents PCT/EP93/01232, WO94/26875 or EP 97/02703 or in the articles mentioned below:
xe2x80x9cAutologous lymphocytes prevent the death of monocytes in culture and promote, as do GM-CSF, IL-3 and M-CSF, their differentiation into macrophagesxe2x80x9d. (Lopez M., Martinache Ch., Canepa S., Chokri M., Scotto F., Bartholeyns J.; J. of Immunological Methods, 159: 29-38, 1993);
xe2x80x9cImmune therapy with macrophages: Present status and critical requirements for implementationxe2x80x9d (Bartholeyns J., Romet-Lemonne J-L., Chokri M., Lopez M.; Immunobiol., 195: 550-562, 1996);
xe2x80x9cIn vitro generation of CD83+ human blood dendritic cells for active tumor immunotherapyxe2x80x9d (Thurnher M., Papesh C., Ramoner R., Gastlt G. and al.; Experimental Hematology, 25: 232-237, 1997);
xe2x80x9cDendritic cells as adjuvants for immune-mediated resistance to tumorsxe2x80x9d (Schuler G. and Steinman R. M.; J. Exp. Med., 186: 1183-1187, 1997).
All these patents applications and articles are included herein for references.
They can be activated by IFN-xcex3 at the end of culture to obtain in particular cytotoxic macrophages. They can be centrifuged to be concentrated and purified before resuspension in isotonic solution.
Monocyte derived cells (MDCs) can either be killer macrophages, phagocytozing cells, growth factors and cytokines releasing cells, or dendritic cells according to their conditions of differentiation. Dendritic cells can for example be obtained as described in xe2x80x9cIn vitro generation of CD83+ human blood dendritic cells for active tumor immunotherapyxe2x80x9d (Thurnher M., Papesh C., Ramoner R., Gastlt G. and al.; Experimental Hematology, 25: 232-237, 1997) and xe2x80x9cDendritic cells as adjuvants for immune-mediated resistance to tumorsxe2x80x9d (Schuler G. and Steinman R. M.; J. Exp. Med., 186: 1183-1187, 1997), and EP 97/02703.
In addition, activated monocyte derived cells (macrophages) can be used to deliver therapeutic agents to tumor or infectious sites.
One of the aims of the invention is to provide a combined preparation of active substances under the form of individual components for the simultaneous separate or sequential use, in the treatment of cancer or of infectious diseases.
Another aim of the invention is to provide a method for the treatment of residual cancer resistant to chemotherapy.
Another aim of the invention is to provide a method for the treatment of infectious diseases resistant to antibiotic treatment.
The invention relates to a combined preparation containing, as active substance, the following individual components, in the form of a kit-of-parts:
monocyte derived cells, particularly cytotoxic macrophages,
chemotherapy or immunotherapy drugs,
for the simultaneous, separate or sequential use, for the treatment of cancer or infectious diseases.